Process for the preparation of cholanic acid derivatives



Patented Mar. 9, 1954 UNITED STATES PATENT QFFICE PROCESS FOR. THE PREPARATION or GHOLANIC. ACID DERIVATIVES,

No Drawing. Application August 19, 1950, Serial No. 180,505

20 Claims. 1

The present invention relates to the manufacture of intermediates suitable for the preparation of compounds of therapeutic activity, or of compounds which can be converted into substances of therapeutic value, and particularly for the preparation of the compound known as Kendalls Compound E (cortisone).

It is the general object of our invention to provide an improved and simplified procedure for the preparation of 3-hydroxy-12-keto and 3-hydroxy-'7,l2-diketo cholanic acids of saturated or unsaturated character, whereby the number of steps involved is reduced and likewise the time required, and the yield considerably in- American Chemical Society 65, 5.49v (1943) who succ-inylated desoxycholic acid, isolated the half-.- succinate, and then oxidized it and isolated the 12-keto compound. By this. procedure the number of steps was reduced, but the yields were still not entirely satisfactory.

We have found that the acylation of the B-hydroxyl of the steroid acid can be carried out under conditions such that the; reaction mixture containing the 3-ester of the steroid acid can be oxidized directly with chromic acid upon dilution with acetic or other lower aliphatic, acid and sulfuric or other strong acid, that is, without prior isolation of the ester, if the reactions creased over prior procedures. 15 occur in the presence. of an organi solvent base A specific object of the invention is to provide l e pyridine. This was quite unexpected or p ified and more efiicient process constituttwo reasons. In the first pla e, py id e i a ing the initial steps in the synthesis of cortisone. relative y oxidizable compound. nd ts. pr s n Other objects and advantages of the invention in the mixture to be oxidized WQLI Cl the or will appear from the following more detailed be undesirable. In the second, plafie, it is well description thereof. known that pyridine forms salts with chromic The process of the present invention is genacid, and it was to be expected either that the erally applicable for the manufacture of nu- OXidiZiIlg Power of the Chromic acid would be clearly saturated and unsaturated 3-hydroxydecreased, or, if the chromic acid should be freed iZ-keto-cholanic acids, including the A9J1- by the sulfuric acid, that then the pyridine would cholenio acids, wherein a keto group ma be be oxidized. We have, however, found that the present also in the 7-position, whether or not Oxidation b a o Proceed smoothly and a hydrocarbon group is present between the c that the crude ketonic product can be isolated boxylic group and the 17-carbon, and th s inin an almost quantitative yield. eludes the nor-, bisnor-, and etio-acids. The The acyl group in the 3-IJ0Siti0n y b of invention will, however, be further described in ny su ta e typ a its un t is t p t t detail, and by way of example, in connection t hyd xyl r up a a nst th ox dizin a ent. with the conversion of desoxycholic and cholic It y be al p aromatic, cycloaliphatic acids into the 3-hydroxy 1 2-keto and 3-hydroxyaralkyl in character, and it may be monobasic 7,12-diketo cholanic acids, but it will be underr p si pl s of isfa t y a yl stood that,the procedure described can be emo p a y p y y Succihyl, ployed also with the other cholanic and also henZoyl, pbenzene sulfonyl, D y the cholem'c acids to produce analogous products. Cyclohexylacetyl, In the e O the po y- In the procedure as described by Kendall basic acids, the ester will preferably be a partial (Journal of Biological Chemistry, 73, 2'11 (1948)) 40 st r, lik a h lf-su y hal -p a t methyl desoxycholate is first prepared fro The following examples illustrate the invendesoxycholic acid in methanol. Thi ester 1 tion in greater detail but are not to be underthen partially benzoylated to protect the 3- Stood as indicating the scop o hydroxyl, the product is isolated, and thereafter Example 1 oxidized and again isolated. Since both the methyl desoxycholate and its 3 -benzoate carry A mixture of 19.6 g. desoxycholic,acid,f5;25 g. methanol of crystallization which must be resuccinic anhydrido. an .5 anhydrou pyr din moved before the benzoylation and oxidation, a refluxed fo one-half hour, and then 00121 6. respectively, there are actually no fewer than and diluted with a solution of 9.5 cc, sulfuric eight operations involved in this sequence, and acid in 200 cc. acetic acid. the over-all yield is still further adversely afiected The mixture was further cooled, to 13 to, 15 by failure to remove the last traces of methanol. C. and to it was added a Solution 1333 g, CrOs These intermediate products are, moreover, in 5 cc. water in two portions. At the end .of i l o c y t lli A, better. procedure is o e hour the temperature was permitted, o ise described by schwenk et al. (Journal of the to 15 to 20 for one-hallhour and'the reaction mixture was poured into 2.5 l. or water. The white product was collected, washed thoroughly and dried. There was obtained 23.8 g. (97%) of the 12-keto compound, melting from 230 to 235 C.

Example 2 By reactions as described in Example 1, 1176 g. of pure desoxycholic acid, 315 g. succinic anhydride and 900 cc. pyridine were refluxed until succinylation at the 3-position was substantially complete (about 1 hour), and the solution of the half-ester was then poured into 14 liters of acetic acid and oxidized at 20:2" 0. with 230 g. C'rOa, 600 cc. concentrated sulfuric acid and 1300 cc. water. After stirring for about two hours, the mixture was cautiously diluted to 100 l. with water, the product was collected on a large filter, washed thoroughly with water and dried at 80 C. The yield was 1330 g. (95% of theory) of white material with specific rotation of a 1% solution in acetone of +96 and melting range from 228 to 232.

Example 3 By the procedure described in Example 1, using 20.4 g. cholic acid instead of the desoxycholic acid, and oxidizing with 7.7 g. or" CrO3 instead of 3.83 g., and proceeding otherwise as described in such example, the half-succinate of 3-hydroxyl-7,12-diketocholanic acid was obtained in good yield.

Example 4 By reactions as described in Example 1, using 5.1 g. acetic anhydride in place of the succinic anhydride and allowing the oxidation to proceed for a total of two hours at 15 to there were obtained 21.1 g. of crude 3-acetoxy-12-ketocholanic acid melting about 180-190".

Example 5 By the reactions as described in Example 1, using cc. concentrated hydrochloric acid in place of the sulfuric acid, the same 12-keto compound melting at 228 to 234 was obtained in 23 g. yield.

Although we prefer to employ pyridine for providing the basic conditions under which the 3-acylation takes place, other solvent organic bases can be employed, like lutidine, collidine,

quinoline, dimethylaniline, etc.

In place of acid anhydride, the acid chloride can also be used to efiect acylation. In general, approximately equivalent proportions of the steroid hydroxy acid and of the acylating agent can be employed, but an excess of the latter may be used.

The oxidation of the 3-ester, as shown by the above examples, is carried out without first isolating such ester. While the presence of the sul furic acid is preferred, other strong acids can be used, such as trichloroacetic, fluorosulfonic, hydrochloric, perchloric, etc. In place of oxidation with chromic acid, other methods of oxidation can be used. In the oxidation of the cholenic acids, the nuclear double bond can be intermediately protected in known manner, as by bromination, followed by debromination after the oxidation.

The 3-esters of the cholanic and cholenic acids, including their lower homologues or 17-degradation products, can be employed as such in the :nextstepof any ,desired process, for example to 4 effect dehydrogenation at C9 or Cu, or they may be saponified in aqueous or alcoholic alkali to restore the S-hydroxyl.

We claim:

1. Process for the manufacture of steroid keto acids, which comprises reacting a member of the group consisting of saturated and unsaturated 3,12-dihydroxy cholanic acids in the presence of an organic solvent base with a sufficient amount of a carboxylic acid acylating agent to form the 3-ester, and mixing the entire reaction solution with an oxidizing agent to effect replacement of the 12-hydroxyl with ketonic oxygen.

2. Process for the manufacture of steroid keto acids, which comprises reacting a member of the group consisting of saturated and unsaturated 3,12-dihydroxy cholanic acids in solution in pyridine with a suificient amount of a carboxylic acid acylating agent to form the 3-ester, and mixing the entire reaction solution with an oxidizing agent to effect replacement of the l2-hydroxyl with ketonic oxygen.

3. Process according to claim 1, wherein the oxidizing agent is chromic acid in acetic acid solution.

4. Process for the manufacture of steroid keto acids, which comprises reacting a member of the group consisting of saturated and unsaturated 3,12-dihydroxy cholanic acids in pyridine solution with a sufiicient amount of a carboxylic acid acylating agent to form the 3-ester, mixing the entire reaction solution with chromic and acetic acids to effect replacement of the 12-hydroxyl with ketonic oxygen, and separating the keto steroid formed.

5. Process for the manufacture of steroid keto acids, which comprises reacting a 3,12-dihydroxy cholanic acid in pyridine solution with a sufiicient amount of succinic anhydride to form the 3-partial ester, mixing the entire reaction solution with chromic and acetic acids to efiect replacement of the 12-hydroxyl with ketonic oxygen, and separating the keto steroid formed.

6. Process according to claim 1, wherein the cholanic acid is cholic acid.

7. Process according to claim 5, wherein the cholanic acid and succinic anhydride are employed in approximately equimolecular proportions.

8. Process according to claim 5, wherein the oxidation mixture is cooled to below room temperature.

9. Process according to claim 5, wherein the oxidation mixture is cooled to about 13-15" C.

10. Process according to claim 5, wherein the oxidation mixture, on completion of the oxidation, is poured into water and the precipitated product separated, washed and dried.

11. Process according to claim 5, wherein the oxidation proceeds for about one hour with cooling to about 1315 C., and for a further halfhour without cooling.

12. Process according to claim 11, wherein the cholanic acid is desoxycholic acid.

13. Process according to claim 5, wherein the cholanic acid is desoxycholic acid.

14. Process for the manufacture of 12-keto steroid acids, which comprises reacting 1 mole of a 3,12-dihydroxy cholanic acid with approximately 1 mole of succinic anhydride in about 300 cc. of anhydrous pyridine under reflux, cooling the reaction solution, adding thereto about 4 liters of acetic acid, cooling the mixture to below room temperature, adding a solution of chromic oxide in water, and when the oxidation is complete, pouring the reaction mixture into water and separating the precipitate.

15. Process according to claim 14, wherein the cholanic acid is desoxycholic acid.

16. Process according to claim 14, wherein the amount of chromic oxide is approximately 7'7 g. in about 100 cc. of water.

17. Process according to claim 1, wherein the oxidizing agent comprises a mixture of chromic, acetic and sulfuric acids.

18. Process according to claim 1, wherein the oxidizing agent comprises a mixture of chromic, acetic and hydrochloric acids.

19. Process according to claim 1, wherein the acylating agent is acetic anhydride.

20. Process for the manufacture of nuclearly unsaturated steroid keto acids, which comprises brominating a nuclearly unsaturated 3,12-dihydroxy cholanic acid in the presence of an organic solvent base, reacting the brominated acid, dissolved in said base, with a sufficient amount of a carboxylic acid acylating agent to form the 3-ester, mixing the entire reaction solution with an oxidizing agent to eifect replacement of the 12-hydroxy1 with ketonic oxygen, and isolating the 12-keto acid either before or after debromination for effecting regeneration of the nuclear double bond.

TEMPLE CLAYTON.

EMANUEL B. HERSHBERG.

BERNARD SCHOEN.

References Cited in the file of this patent UNITED STATES PATENTS Number 

1. PROCESS FOR THE MANUFACTURE OF STEROID KETO ACIDS, WHICH COMPRISES REACTING A MEMBER OF THE GROUP CONSISTING OF SATURATED AND UNSATURATED 3,12-DIHYDROXY CHOLANIC ACIDS IN THE PRESENCE OF AN ORGANIC SOLVENT BASE WITH A SUFFICIENT AMOUNT OF A CARBOXYLIC ACID ACYLATING AGENT TO FORM THE 3-ETHER, AND MIXING THE ENTIRE REACTION SOLUTION WITH AN OXIDIZING AGENT TO EFFECT REPLACEMENT OF THE 12-HYDROXYL WITH KETONE OXYGEN. 